Triad of severe abdominal pain, inappropriate antidiuretic hormone secretion, and disseminated varicella-zoster virus infection preceding cutaneous manifestations after hematopoietic stem cell transplantation: utility of PCR for early recognition and therapy

A hematopoietic stem cell transplant recipient developed abdominal pain, pneumatosis intestinalis, hepatitis, pancreatitis, and inappropriate antidiuretic hormone secretion. Blood for varicella-zoster virus (VZV) DNA polymerase chain reaction was positive. She was treated with acyclovir and subsequently developed VZV antigen-positive zoster. Detection of VZV DNA in blood may be useful for early diagnosis in immunocompromised hosts who present with zoster without skin lesions.     

��ͯ�����ϰ���ƶѪ��Ѫ��ϸ����ֲ�󲢷���ɢ�ʹ�״����3�����沢���׸�ϰ

??Objective To discuss the diagnosis, high risk factors, prevention and treatment of disseminated varicella zoster virus??VZV?? infection after allogeneic hematopoietic stem cell transplantation??allo-HSCT?? in children with aplastic anemia??AA??. Methods A retrospective analysis was made about the clinical data of 3 children with disseminated VZV infection after allo-HSCT for AA. Results Three children, aged 10??13 years old??who didn’t present graft-versus host disease??GVHD?? after transplantation, were given single drug as anti-viral prophylaxis of VZV. During the period of prophylaxis, none of them developed VZV reactivation but they showed symptoms of disseminated VZV infection after discontinuation of anti-viral prophylaxis. All of them were treated with intravenous ganciclovir, oral valaciclovir combined with external application of penciclovir and with gamma globulin until the rush crusted, and eventually all of them recovered well. Conclusion Patients with allo-HSCT for aplastic anemia are at high risk of developing disseminated VZV infection and they have high incidence of mortality and poor prognosis. We recommend anti-viral prophylaxis after allo-HSCT for prevention?? and reduced dose of immunosuppressive drugs and combination use of ganciclovir, valaciclovir and gamma globulin when patients present symptoms of VZV infection.     

儿童再生障碍性贫血造血干细胞移植后并发播散型带状疱疹3例报告并文献复习

目的 探讨儿童再生障碍性贫血（AA）造血干细胞移植（HSCT）后并发播散型带状疱疹的诊断、高危因素、预防及治疗措施。方法 回顾性分析2014年12月至2015年9月中山大学孙逸仙纪念医院儿科收治的3例AA患儿接受全相合非血缘相关供者HSCT后予免疫抑制剂治疗期间出现播散型带状疱疹的临床资料。结果 3例患儿年龄分别为13、12和10岁,移植后未出现移植物抗宿主病,予抗病毒药物单药预防水痘-带状疱疹病毒（VZV）期间均未出现VZV再激活,在HSCT后4.0、5.5和8.0个月停用抗病毒药物,分别在停用抗病毒药物后13.0、10.5和3.0个月出现皮肤播散型带状疱疹,予静脉更昔洛韦联合口服伐昔洛韦及外用喷昔洛韦抗病毒治疗至皮疹结痂,并予丙种球蛋白治疗,均完全治愈。结论 接受HSCT的AA患者是播散型带状疱疹的高发人群,其发病率高、病情严重且病死率高。移植后予预防性抗病毒处理,出现播散型带状疱疹时减少免疫抑制剂量,联合更昔洛韦、伐昔洛韦及丙种球蛋白治疗,可明显改善疗效。     

Fulminant hepatitis due to varicella zoster virus in a girl with acute lymphoblastic leukemia in remission: report of a case and review

The authors describe a 4-year-old girl with acute lymphoblastic leukemia in remission who developed fulminant hepatic failure due to varicella-zoster virus (VZV). Diagnosing VZV visceral infection in immunocompromised patients is often difficult due to atypical clinical presentation with few or no skin lesions and severe abdominal or back pain. Prompt initiation of empirical treatment with acyclovir and VZV immunoglobulin pending results of the serum polymerase chain reaction for VZV is warranted in this clinical setting.     

Antiviral therapy for varicella and herpes zoster

Varicella-zoster virus (VZV) causes 2 clinical illnesses, varicella (chickenpox) and herpes zoster (shingles). The purpose of this review is to describe the role of antiviral therapy in the treatment of VZV infections in healthy and immunocompromised children. Acyclovir is the drug of choice for varicella and herpes zoster. The route of administration may be intravenous or oral, depending on the immunocompetence of the host. The clinical impact of acyclovir therapy is related directly to its use early in the clinical course and to the likely susceptibility of the patient to severe or life-threatening VZV infection. Patients who have the most clinical benefit are otherwise healthy adolescents with varicella infection and high-risk populations of immunocompromised children who have varicella or herpes zoster. The morbidity and mortality of VZV infections are reduced substantially by initiating acyclovir treatment early in the course of the disease.     

Infection à BK Virus après allogreffe de celluleshématopoïétiques. A propos d'un cas

Polyomavirus hominis 1, better known as BK virus (BKV), infects up to 90% of the general population. Significant clinical manifestationscan be seen in immunocompromised patients. We report a case of haemorragic cystitis likely due to BKV in a child after allotransplantation of hematopoietic stem cells. A 10-year old boy with poor-prognosis acute T lymphoblastic leukaemia underwent cord blood allogeneic stem cell transplantation while in his first relapse. Macroscopic haematuria and low back pain occurred by day 95, in the context of acute graft versus host disease and pulmonary aspergillosis. Histopathologic examination showed a cytopathogenetic effect consistent with the diagnosis of BKV infection. Urinary PCR was positive for BKV. Treatment with cidofovir was followed by a marked improvement of urinary symptoms. The current understanding, diagnosis, and treatment of BKV-associated infection is discussed.     

Zona in children]

Herpes zoster is the clinical consequence of a late reactivation of the varicella zoster virus (VZV). It infects mainly the elderly, but pediatric cases are not uncommon. It occurs mostly in immunocompromised children, or in infancy after reactivation of latent VZV infection acquired transplacentally during intrauterine life. Rarely, herpes zoster occurs in otherwise normal children, especially following varicella during the first year of life. Clinical presentation of herpes zoster in children is identical to that of adult, with usually a benign course. The impairment of cellular and non specific immunity (Natural Killer cells) appears to have a particular role in the occurrence of herpes zoster. Treatment of the usual form comprises antiseptic measures and prevention of pruritus. In immunocompromised children, the infection is generally severe and disseminated, and can result in high rates of morbidity and mortality, thus requiring specific intravenous antiviral therapy with antiviral drugs such as acyclovir without delay. There is no single approach towards VZV infection prevention in immunocompromised hosts. Vaccination with live attenuated varicella vaccine, has proved to be efficient and safe in immunocompromised children.     

Intermittent oral trimethoprim/sulfamethoxazole on two non-consecutive days per week is effective as Pneumocystis jiroveci pneumonia prophylaxis in pediatric patients receiving chemotherapy or hematopoietic stem cell transplantation

Pneumocystis jiroveci pneumonia (PCP) is a serious complication in patients receiving chemotherapy or hematopoietic stem cell transplantation. Current recommendations for trimethoprim-sulfamethoxazole (TMP-SMZ) dosing as PCP prophylaxis in immunocompromised patients are based on either daily dosing or dosing three consecutive days per week. We report our experience of prophylaxis with TMP-SMZ twice daily on two non-consecutive days per week in 145 immunocompromised children with hematologic disorders, cancer, or metabolic disorders following chemotherapy or hematopoietic stem cell transplantation. There were no breakthrough cases of PCP. We therefore conclude our prophylaxis regimen is effective against PCP in immunocompromised children.     

Oral BVDU treatment of varicella and zoster in children with cancer

In the period June 1980–April 1983, 21 children with malignant discase were admitted because of an intercurrent varicella or zoster infection. They were treated with the new antiviral drug BVDU [(E)-5-(2-bromovinyl)-2-deoxyuridine]. The drug was administered orally at a dose of 15 mg/kg per day for 5 days. All our patients responded promptly to BVDU treatment and recovered completely from their varicella or zoster infections without complications. No toxic side-effects due to the drug were observed.Abbreviations BVDU bromovinyldeoxyuridine - HSV-1 herpes simplex virus type 1 - VZV varicella-zoster virus - SGPT glutamic-pyruvic transaminase - SGOT glutamicoxaloacetic transaminase     

Comparison of Acyclovir and Vidarabine in Immunocomtxomised Children with Varicella-Zoster virus Infection

Intravenous acyclovir and vidarabine were compared in the treatment of varicella-zoster virus (VZV) infection in 25 immunocompromised children - 13 with acute lymphocytic leukemia, three with other types of cancer, two with immunodeficiency and in seven undergoing prednisolone treatment. Thirteen had varicella and 12 had herpes zoster. Acyclovir was given intravenously to five patients with varicella and to four with herpes zoster at a dose of 5–10 mg/kg every eight hours. Vidarabine was given intravenously to eight patients with varicella and to eight with herpes zoster at a dose of 10 mg/kg/day. In varicella, vidarabine significantly shortened the time from the start of treatment to cessation of new lesion formation compared with acyclovir. However, there was no significant difference in time to complete crusting between the two treatments. In herpes zoster, acyclovir significantly shortened the time from the onset of the skin lesions to complete crusting. A slight raise of GOT in two cases was reported. While acyclovir and vidarabine were equally effective for VZV infection, in herpes zoster acyclovir was more effective.     

Prevention or modification of varicella using zoster immune plasma.

Zoster immune plasma (ZIP) was given to 31 susceptible immunocompromised children one to seven days (median, two days) following household, playmate, or hospital exposures to varicella. The average amount of ZIP transfused was 7 ml/kg. Twenty-one children did not develop varicella or persistent antibodies to varicella-zoster virus (VZV). Eight (26%) of the 31 contracted clinical varicella. Seven cases were mild, but in one child, who was given ZIP seven days after exposure, visceral disease developed and the child died. Two children had subclinical varicella that was documented by persistence of VZV antibodies for at least ten months after passive immunization. Because none of the 30 children given ZIP one to six days following exposure had severe varicella, we conclude that ZIP is effective in preventing or modifying varicella in immunocompromised patients if given shortly after exposure.     

异基因造血干细胞移植后乙型肝炎病毒感染2例临床干预并文献复习

目的 加强对造血干细胞移植中HBV感染的重视,注重早期干预,提高移植成功率。方法 回顾性分析97例异基因造血干细胞移植患儿的临床资料,通过对2例HBV感染的诊治体会结合文献复习。结果 2001年5月至2008年5月在上海交通大学附属上海儿童医学中心接受异基因造血干细胞移植的97例患儿中,2例分别在移植后41 d（病例1）、15个月（病例2）发生HBV感染。病例1移植前肝功能正常,乙肝二对半检查阴性,回顾性分析发现该患儿移植时HBV正处于潜伏状态（HBV DNA 1.17×106 copies·mL-1）。该患儿乙肝来势凶猛,移植后41～43 d出现巩膜明显黄染并伴大量腹水,移植后46 d迅速发展至肝、肾功能衰竭,出现少尿,凝血酶原时间38.4 s,部分凝血酶原时间>120 s,凝血酶时间>100 s,Cr 251 μmol·L-1,ALT 3 195 U·L-1,血清总胆红素7 mg·L-1,直接胆红素2.8 mg·L-1,HBV DNA 1.08×108 copies·mL-1,经拉米夫定等积极治疗2周后好转。移植后130 d 随着移植物抗宿主病（GVHD）的复燃和免疫抑制药物的加强应用,HBV再度活跃,HBV DNA从原已控制的3.50×104 copies·mL-1逐升至2.05×106 copies·mL-1,移植后315 d出现HBV YMDD（+）变异株,遂予阿德福韦酯联合治疗至今(移植后3.5年),目前肝、肾功能正常。病例2白血病起病初及干细胞移植前均示HBs Ab(+)、HBc Ab(+)、HBe Ab(+),ALT和HBV DNA正常,移植后12个月发生慢性广泛性GVHD,加强抗排异治疗后于移植后15个月复查发现：ALT 168 U·L-1,HBV DNA升至5×108 copies·mL-1,出现HBs Ag（+）和HBe Ag（+）。予拉米夫定治疗至移植后4.5年,目前ALT 40～80 U·L-1,HBV DNA 1×103～1×104 copies·mL-1。结论 乙肝在移植患儿中并不少见,长期的免疫抑制治疗常使病情反复,加强病毒监测、重视早期干预至关重要;移植前HBV DNA 检测有助于发现潜伏期患儿;HBs Ab(+)、HBe Ab(+)和HBc Ab(+)患儿在强烈免疫抑制下仍有HBV复燃的风险。     

Expression of interleukin-2 receptor, CD25, on CD4 lymphocytes in response to varicella-zoster virus antigen among patients with malignancies immunized with live attenuated varicella vaccine

BACKGROUND: Varicella in an immunocompromised host is often serious or life threatening. A live attenuated varicella vaccine was developed in Japan. It has been reported that the varicella vaccine is safe and highly protective against severe varicella in children with leukemia and other malignancies. It is important to investigate the persistence of varicella-zoster virus (VZV)-specific cell-mediated immunity in patients with malignancies who have been immunized with varicella vaccine. METHODS: Sixteen patients with malignancies and 11 controls had been immunized with attenuated live varicella vaccine. The duration from vaccination to the study ranged from 2 to 16 years (mean 10 years). Nineteen patients and 20 controls had experienced natural varicella infection. Peripheral blood mononuclear cells (PBMC) from patients and controls were cultured with VZV antigen for 6 days and the percentage of cluster of differentiation antigen (CD)25 among CD4 lymphocytes was calculated by flow cytometry. CONTROLS: The percentage of CD25-positive cells among CD4 lymphocytes significantly increased in response to the VZV antigen in vaccinated patients and patients with past natural varicella infection as observed in the controls. CONCLUSIONS: These data show that VZV-specific cell-mediated immunity is induced and persists in patients with malignancies after immunization with live varicella vaccine.     

Atypical varicella zoster infection associated with hemophagocytic lymphohistiocytosis

Two adolescents, on immunosuppressive therapy for graft‐versus‐host disease, developed hemophagocytic lymphohistiocytosis (HLH) after varicella zoster virus (VZV) reactivation. In the absence of dermatome restricted characteristic skin lesions, VZV reactivation was not immediately recognized and treatment with acyclovir was delayed. The first patient developed optical neuritis and died 2 months after the VZV episode due to massive intracranial hemorrhage. The second patient presented with severe abdominal pain and pancreatitis, followed by atypical skin eruptions, which prompted a faster diagnosis. Both patients recovered from their HLH, the first patient being successfully treated with immunosuppressive agents and the second with VZV treatment only. These two cases demonstrate the difficulties in recognizing VZV reactivation, and in order to start adequate and timely treatment, the need to consider VZV as a possible cause of HLH in severely immunocompromised patients. Pediatr Blood Cancer 2009;53:226–228. © 2009 Wiley‐Liss, Inc.     

卡泊芬净治疗儿童血液病化疗或移植过程中真菌感染35例临床分析

目的评估卡泊芬净治疗儿童血液病化疗或造血干细胞移植（HSCT）过程中真菌感染的疗效和安全性。方法2010年4月-2013年3月我科35例血液病患儿化疗或HSCT过程中出现真菌感染,予卡泊芬净治疗,第1天予单次负荷剂量70mg／（m2·d）（实际剂量不超过70mg／d）,随后维持剂量50mg／（m2·d）（实际剂量不超过70mg／d）,回顾性分析其疗效和安全性。结果卡泊芬净治疗35例儿童血液病化疗或HSCT过程真菌感染总有效率为71％（25／35）,毒副作用发生率为3％（1／35）。其毒副作用表现为可逆性肝功能损害,停药后好转。结论卡泊芬净有效率高,安全性好,可以作为儿童血液病化疗或HSCT过程中真菌感染治疗的选择。     

The impact of RSV,adenovirus, influenza,and parainfluenza infection in pediatric patients receiving stem cell transplant,solid organ transplant,or cancer chemotherapy

RVIs are a significant cause of morbidity and mortality in immunocompromised children. We analyzed the characteristics and outcomes of infection by four respiratory viruses (RSV, adenovirus, influenza, and parainfluenza) treated at a pediatric tertiary care hospital in a retrospective cohort of patients who had received cancer chemotherapy, hematopoietic stem cell, or SOT. A total of 208 infections were studied among 166 unique patients over a time period of 1993–2006 for transplant recipients, and 2000–2005 for patients with cancer. RSV was the most common respiratory virus identified. There were 17 (10% of all patients) deaths overall, of which 12 were at least partly attributed to the presence of a RVI. In multivariate models, LRT symptoms in the absence of upper respiratory symptoms on presentation (OR 10.2 [2.3, 45.7], p = 0.002) and adenoviral infection (OR 3.7 [1.1, 12.6], p = 0.034) were significantly associated with poor outcome, defined as death or disability related to RVI. All of the deaths occurred in patients who had received either solid organ or HSCT. There were no infections resulting in death or disability in the cancer chemotherapy group.     

Outcome of hematopoietic stem cell transplantation in severe combined immune deficiency with central nervous system viral infection

BACKGROUND: Patients with severe combined immunodeficiency and preexisting viral pneumonitis formally had a poor outcome from hematopoietic stem cell transplantation. With inhaled steroid and antitumor necrosis factor alpha antibody treatment, results improved. The poor outcome of patients with viral central nervous system infection prompted this retrospective single center review. RESULTS: Eight of 71 patients with severe combined immunodeficiency transplanted since 1987 were identified with viral central nervous system infection (adenovirus [1], cytomegalovirus [2], Epstein-Barr virus [2], parvovirus [1], varicella zoster virus [1], human herpesvirus 6 [1]). Nonspecific neurologic symptoms included drowsiness, irritability, head lag, fisting and floppiness. Later symptoms included unresponsiveness, apnea, posturing, hypotonia, hyperreflexia and seizures. All had neuroradiologic investigations. Only one had an initially normal computed tomography scan. Magnetic resonance image abnormalities included cerebral atrophy, basal ganglia changes, diffuse leukoencephalopathy, and multifocal mass lesions. Five patients had virus identified from cerebrospinal fluid by polymerase chain reaction and brain tissue examination from 3 patients identified human herpesvirus 6, adenovirus type 41 and varicella zoster virus. Three children remain alive, 2 received replete marrow and one remains untransplanted. Others who received T cell depleted marrow died of neurologic sequelae. CONCLUSION: Outcome of viral central nervous system infection after hematopoietic stem cell transplantation for severe combined immunodeficiency is poor, particularly associated with T cell depleted marrow.     

Bacterial meningitis from Rothia mucilaginosa in patients with malignancy or undergoing hematopoietic stem cell transplantation

Opportunistic infections contribute to morbidity and mortality of patients undergoing hematopoietic stem cell transplantation and treatment for malignancies. Rothia mucilaginosa, a gram-positive bacterium, is responsible for rare, but often fatal meningitis in severely immunocompromised patients. We describe two cases of meningitis from discrete strains of R. mucilaginosa on our pediatric bone marrow transplant unit, summarize the published cases of R. mucilaginosa meningitis in oncology and stem cell transplant patients, and provide updated recommendations regarding the use of antibiotic therapy in this patient population.     

New antifungal drugs and the pediatric cancer patient: current status of clinical development

Invasive mycoses are important causes for treatment related morbidity and mortality in severely immunocompromised pediatric patients with hematological malignancies or hematopoietic stem cell transplantation. The past decade has witnessed a major expansion of antifungal drug research, which has resulted in the development of the novel class of echinocandin lipopeptides (anidulafungin, micafungin, caspofungin) and a new generation of antifungal triazoles with improved pharmacological properties (posaconazole, ravuconazole, voriconazole). Whereas caspofungin and voriconazole have been licensed in the European Union, the United States, Canada and several other countries throughout the world, posaconazole, ravuconazole, anidulafungin and micafungin are under regulatory review or in advanced stages of clinical development. Caspofungin and voriconazole are increasingly prescribed in pediatric patients, although pediatric dosage finding and safety evaluations have not been completed. This article reviews the clinical pharmacology of the new antifungal agents and the status of their clinical development in immunocompromised pediatric patients.     

原发性免疫缺陷病造血干细胞移植患儿呼吸道合胞病毒感染特征

目的 了解原发性免疫缺陷病(PID)患儿在造血干细胞移植过程中呼吸道合胞病毒(RSV)感染临床特征和转归.方法 移植前以及移植后连续收集白2009年4月到2010年9月于重庆医科大学附属儿童医院接受造血干细胞移植的9例患儿鼻咽吸取物(NPA),采用荧光定量PCR法检测RSV,对阳性标本进行病毒分离,扩增G基因用于遗传进化分析,并收集临床资料分析其临床感染特征.结果 9例患儿中3例检出RSV,检出率为33.3%,且在3例阳性患儿NPA中多次分离出RSV,并通过G基因序列分析发现,3例患儿均感染RSV B亚型毒株,在体内持续复制数月之久.其临床表现均为肺炎,未见明显重症倾向.1例患儿抗病毒治疗,3例患儿均静脉滴注丙种球蛋白(IVIG),均好转出院.而同期于该院呼吸病房因急性下呼吸道感染(ALRTI)住院儿童RSV感染率仅为20%,且以B亚型为优势流行株,10例RSV B亚型同期呼吸科病房普通患儿临床症状与PID造血干细胞移植患儿相似.结论 PID造血干细胞移植患儿更易感染RSV,且可在体内可持续复制数月,及时诊断和治疗,随着免疫功能逐步重建,RSV感染多可恢复.

Abstract：

Objective To understand the clinical characteristics and outcome associated with respiratory syncytial virus(RSV)infection in hematopoietic stem cell transplantation(HSCT)recipients with primary immunodeficiencies(PIDs).Method Nasopharyngeal aspirate samples were collected consecutively before and after HSCT from 9 recipients from Apr. 2009 to Sep.2010 and analyzed for the presence of RSV using real-time polymerase chain reaction assay.To further verify the presence of the virus, positive samples for PCR were isolated for RSV.RSV G gene was amplified,sequenced and used for phylogentic analysis. Result The presence of RSV was detected in 3 out of 9 children. The viral replication in all the patients was prolonged for months. All the 3 patients with RSV infection were treated with intravenous immune globulin (IVIG) and one was treated with antiviral medication. All patients survived and achieved successful immune reconstitution. Conclusion This study indicates that the HSCT recipients with PID are at increased risk for RSV infection. RSV can shed for months after the initial infection and the patients recover with the course of immune reconstitution.